A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML)
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Objective Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML.Methods MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID).Results 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7μM·h,Cmax 1.5μM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L.Conclusions The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.
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MK-8242 exhibited a strong inhibitory effect on wild-type PPTP cells with an IC50 value of 0.07 μM, but had weak inhibitory effects on TP53-mutant PPTP cells with an IC50 value greater than 10 μM, indicating a selectivity of more than 100 times.
“It exhibited a strong inhibitory effect on wild-type PPTP cells with an IC50 value of 0.07 μM, but had weak inhibitory effects on TP53-mutant PPTP cells with an IC50 value greater than10 μM), indicating a selectivity of more than 100 times.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [377]
In vivo studies demonstrated that MK-8242 delayed tumor growth by a factor of two or more in 10 of 17 solid tumor xenografts containing wild-type TP53, but had no effect on osteosarcoma xenografts with low TP53 expression.
“In vivo studies demonstrated that MK-8242 delayed tumor growth by a factor of two or more in 10 of 17 solid tumor xenografts containing wild-type TP53, but had no effect on osteosarcoma xenografts with low TP53 expression.377–380”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [377]
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- Authors
- Ravandi, F., Gojo, I., Patnaik, M. M., Minden, M. D., Kantarjian, H., Johnson-Levonas, A. O., Fancourt, C., Lam, R., Jones, M. B., Knox, C. D., Rose, S., Patel, P. S., & Tibes, R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Mayo Clinic (US)
- Princess Margaret Cancer Centre (CA)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Mayo Clinic in Arizona (US)
- Corresponding author
- Ravandi, Farhad
- ORCID
- Venue
- Leukemia Research
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 48
- Pages
- 92-100
- ISSN
- 0145-2126 (ISSN-L)
- PMC
- PMC5408350
- OpenAlex
- W2488647697
- Cited by
- 57
- References
- 44
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 12 · 2018: 6 · 2017: 4 · 2016: 2
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Leukemia Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- acute myeloid leukemia, refractory leukemia, leukemia relapse, dose-limiting toxicity, pharmacokinetics, bone marrow failure, cytopenia, drug safety and tolerability
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cytarabine, Dose-Response Relationship, Drug, Drug Administration Schedule, Enzyme Inhibitors, Female, Humans, Male, Middle Aged, Leukemia, Myeloid, Acute, Survival Analysis, Salvage Therapy, Treatment Outcome, Proto-Oncogene Proteins c-mdm2
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